Salts of 8-halotheophylline and alkali metal salts of amino acids



United States PatCfi SALTS F S-HALOTHEOPHYLLINE AND ALKALI METAL SALTS on AMINO AcrDs James M. Holbert, Lookout Mountain, and .tlrvine W.

Grote, Chattanooga, Tenn., assignors to The Chattanooga Medicine Company, Chattanooga, Tenn, a corporation of Tennessee No Drawing. Application .lune 7, 1951,

Serial No. 230,432

1 Claim. (Cl. 260-253) This invention relates to a therapeutic product, and more particularly to a halo-theophylline-alkali metal salt invention is much superior as a diuretic and has great usefulness in a particular field in which the composition of the patent has no practical value from a remedia standpoint. i

We have now found that by the substitution of an S-halo-theophyiline for theophylline itself, a reaction product of S-halo-theophylline, an aliphatic mono amino carboxylic acid and an alkali metal hydroxide can be formed that has a marked therapeutic eifect'in' the relief of premenstrual tension. estimated at from to sufier from pre-menstrual tension in varying degrees during their menstrual age. These women accumulate water in the tissues during the week preceding the menses in varying amounts, usually from 1 to 5 pounds. Symptoms areheadache, breast fullness and soreness, abdominal distension, low back pain, extreme nervousness, swelling of the ankles, increased appetite, irritability, pelvic pain and a feeling of tension. These symptoms are directly commensurate to the amount of fluid accumulated, or pounds of weight gained. Patients gaining up to two pounds during the week preceding the menses probably do not seek medical relief, but those that gain above two pounds become more conscious of the symptoms and usually do seek relief. Patients gaining from three and one-half to four pounds are almost incapacitated due to the severity of the symptoms from water toxemia. The product of our present invention is most outstanding in the relief of these symptoms. mately one week before onset of menses rarely gain more than one and one-half pounds, and in many cases there is no weight gained whatsoever. Furthermore, patients whoare placed on treatment with our product, even after they have gained weight, have a diuresis within a few hours after beginning treatment, with resultant prompt relief of symptoms. The outstanding feature of our therapeutic product in thetreatment ofpre-menstrual tension is that in most patients it prevents water accumulation without diuresis if the treatment is started early enough so that the patients have no symptom of water toxemia through their premenstrual period.

It is, therefore, an important object of this invention to provide a product having enhanced therapeutic properties in the relief of pre-menstrual tension without, however, causing the patient to become nervous or jittery as is so often the case when theophylline compounds are used.

A large percentage of Women,

Patients to which our product is given approxi- EXAMPLE SQCHLORO-THEOPHYLLINE SODIUM; I

equivalent.

our inventioni EXAMPLE 1.--VBROMO THEOPHYLLINE SODIUM.

his a further important object of this invention to provide a therapeutic product capable of eifectively'unlocking pitressin inducededema in human females. i

Other and further important objects ofgthis invention will become apparent from the following description and appended claim.

The therapeutic product of our invention is prepared by reacting an -8-halo1the0phylline, such *as 8-brorno- ,theophylline or S chloro-thedphylline, with' 'anfaliphatic;

mono-amino carboxylic acid in fwatersolution in the presence of the proper amount of an alkali metalihydroxide, such as sodium or potassium hydroxide; *or'their The aliphatic mono-amino carboxylic acids that are suitabiefor use in the preparationof our product include glycine, alpha-alanine,beta-alanine and glutamic acid. jEqui-molal proportions of v the p8 -halo-theophylline and of the aliphatic amino carboxylic acid compounds are used, and an amount of alkali sufiicient toneutralize the free carboxylic acid groups present, either assodium 'hydroxide or some other. alkali metal compound selected from the group consisting of. sodium-and potassium hy- 'droxides, oxides and basic carbonates. J r 1 V The following" examples will serve to illustrate the Y method of preparing the various therapeutic productsof' I GLYCINATE 4 One mole (259 g.) ofbromo-theophyllineiwas, addedt V to about one liter of water containing one mole ,(40 g.) One mole' f(75 g'.) of glycinei (amino-acetic acid) was added j. slowly, with stirring'and,

* slight warming, sufiicient to eflect complete solution. {l The slightly yellow solution was filteredf and the filtrate evaporated to dryness at reduced pressure and; temper a trim. The solid materiaLwas groundto awhitepowder, 7

giving almost quantitative yields. The physical propertiesofthis product and of the products given in the fol- 'i of sodium' hydroxide.

lowing examples will be found;summariz ed*in Table I.

. i Y- TE Chloro-theophyllineand sodium hydroxide was p pared by'th'e same procedure as given in Example 1,"ex ceptthat 0.1 mole (21.5, g.) of the chloro-theophylline .4

was substitutedfor 0.1 mole"(25.9 g.) ofbromotheo-' phylline g l EXAMPLE 3. BRoMo-THEoPHYL 1Nn PorAs- SIUM GLYCINATE The reaction product of; brorno-theophyllinie, glycine V andpotassium hydroxide was prepared by the same procedure as Example 1,-xce'pt that 0.1 mole,.(5.6 g.) of

potassium hydroxide was substituted for 0.1 mole (4.0 g.) 1 of sodium hydroxide. 1 I,

EXAMPLE 4.''BROM:O-TI-/IEO'PHYLLINE SODIUM V ALANINATE (ALPHA AMINOPROPIONATE) To 0.1 rnole (4.0- g.) of sodium hydroxide in cc. of. Water was added 0.1mole (8.9 g.) of alpha-d1- crystalline material.

7 'ALANINATE V The procedure was the'same as in Example 4, except that 0.1 mole (21.5g.) 'ofchloro-theophylline was sub stituted for 0.1, mole (25.9 g.)' of'bromo theophylline.

Patented Jamel, s

EXAMPLE 6.BROMO-TIIEOPHYLLINE SODIUM BETA ALANINATE (BETA AMINOPROPIONATE) The procedure was the same as in Example 4, except that 0.1 mole (8.9 g.) of beta alanine was substituted for 0.1 mole (8.9 g.) of alpha alanine EXAMPLE 7.BROMO-THEOPHYLLINE SODIUM GLUTAMATE (AMINOSUCCINATE) A mixture of 0.1 mole (25.9 g.) of bromo-theophylline and 0.1 mole (14.7 g.) of glumatic acid in 200 cc. of water was brought into solution by the addition of 0.225 mole (9.0 g.) of sodium hydroxide. The resulting slightly yellow solution was filtered and then evaporated to dryness at a temperature of about 60 C. and under reduced pressure.

The following Table I lists the products of the foregoing examples and gives certain specified data with regard to such products:

Table 1 Percent Ealo- Theophylline SolupH (Dry Basis) Melting bility, Satu- Products Point, gmJlOO rated G 1 o 2 ii Stoma cu- 0 ion lated Found 1. Bromo-theophylline-sodium glycinate 72. B 67. 2 232 16.0 7. 8 2. Chloro-.heophylline-sodium glycinate 68.8 70. 4 235-50 16.5 7. 6 3. Bromo theophylline potassium glycinate 69.6 66. 1 255d 16. 7 8. 3 4. Bromo-theophyllinc-sodium alaninate 70.0 65.5 211 18. 6 8. 5. Ohloro-theophylline-sodium alaninate 65. 8 61. 0 204-5 16. 4 8. 3 6. Bromo-theophylline-sodium beta alaninate 70.0 681 157-60 19. 6 8. 0 7. Brorno-theophylline-sodium glutamate i 57.0 55. 3 215-24. 20 8. 5

In the above Table I, all of the listed products were prepared by the reaction of the 8-halo-theophylline and the aliphatic mono-amino carboxylic acid in equi-molal proportions, and with sufficient sodium or potassium hydroxide to form the salt of the acid used. It is believed that in dry form these products exist as true salts, or salt-like compounds. The existence of true salts is indicated not only by the relatively definite melting points, but also by their solubility characteristics. These halotheophylline sodium salts of the aliphatic mono-amino carboxylic acids 'may, therefore, be represented by the following structural formula:

Degrees Centigrade 1st fraction 230 2nd fraction 233 3rd fraction 232 Since the melting point (with decomposition) of the bromo-theophylline sodium glycinate from which the solution was prepared was 299 C., it is apparent that the crystals obtained in the dilferent fractions were of a true salt and the same as the starting material, viz. bromotheophylline sodium glycinate.

It is also recognized, of course, that many compounds exist as true salts only in their solid states and when dissolved in water are extensively hydrolized into their component parts. The lower pH values of water solutions of the halo-theophylline reaction products of our invention make these products more satisfactory for therapeutic use than the corresponding straight theophylline analogues.

The diuretic action of our products is their most important property in the effective use of the products for the relief of premenstrual tension. The following is a description of our method of testing the diuretic action:

TESTS FOR DIURETIC ACTION We have found that if rats are given tap water perorally on the basis of 5 cc. of water per g. of body weight of each rat, on the average of 100% of the water so given will be excreted as urine over a four-hour period. If, in addition to the water, the rats are each given subcutaneously one-half unit of pitressin (an anti-diuretic drug) only 42% of the water, on the average, will be excreted.

The present test is made upon the basis of the addition to the water and pitressin of the product to be tested for diuretic action. The dosage is on the basis of 0.1 g. of the product per kilogram body weight of the rat, and the product to be tested is added in this proportion to the water and pitressin. In this way, the anti-pitressin action of each of the various products is actually tested in terms of the per cent of water recovery from the rats. The results are shown in Table II, wherein each figure for per cent water recovery represents the average of water recovery from a cage of four rats:

From the above Table II, it will be appreciated that the products of our invention are much more efiective in their anti-pitressin action than theophylline sodium glycinate or ammonium chloride, both of which have been known for their diuretic action. The improvement is more marked if one considers that with pitressin alone the per cent water recovery is 42%, since then the added per cent water recovery for theophylline sodium glycinate is only 32%, whereas the added per cent water recovery for our products, on an average, is better than 58%. Our products thus show nearly 100% greater diuretic action than theophylline sodium glycinate.

The above-described anti-pitressin test serves satisfactorily to measure the diuretic efiect of the product when it is employed in the relief of pre-menstrual tension. In confirmation of this, it has been found that the use of the halo-theophylline products is much more effective for the relief of pro-menstrual tension among human females then the straight theophylline products when administered in comparable dosages and under comparable conditions. This relief of pro-menstrual tension may be explained when it is appreciated that pre-menstrual tension is a symptom-complex related to abnormal water storage during the pro-menstrual period, and it is essentially a water toxemia. The intensity of the symptoms vary directly as the amount of water retained. Relief of the symptoms accompanies the diuresis.

It will be understood that modifications and variations Y amine 1 may be effected without'd pa i g'from thescOP of the V V a v )Refvermceicuedmthc filegoflthisxpatem J novel concepts of the present invention; j i UNITED STATES TS:

We claim as our invention: i v i A therapeutic product consisting essentially of; the salt 1 1 2322352 j h 1----;---- No 1.940 of an S-haIo-theophylline in whichlthe; halo substituent: 2 7 ,5 -I V-:- 1 is selected from the group consistingpf broniineand 2' Cuslc 1 chlorine, and an alkali metal salt of an aliphatic amino v E E ER C carboxylic acid selected from the group consisting of Lesser brug'andfcosnietic Industry, August? 1950,

alanine, glycine and glutamic acid, the 8-halq-theophyl: 1 I v'cil. @7, No.2, pp. :19OInndI277 line and alkali metal salt of the selected aliphatic amino l0 1 1 g j I carboxylic acid being in mole-to-mole ratio. 

